JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms

Schönberg, Kathrin; Rudolph, Janna; Vonnahme, Maria; Yajnanarayana, Sowmya Parampalli; Cornez, Isabelle; Hejazi, Maryam; Manser, Angela R.; Uhrberg, Markus; Verbeek, Walter; Koschmieder, Steffen; Brümmendorf, Tim H.; Brossart, Peter; Heine, Annkristin; Wolf, Dominik

doi:10.1158/0008-5472.can-14-3198

Cited by 160 publications

(136 citation statements)

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“…Previous work has shown that long-term ruxolitinib treatment impairs the maturation and cytolytic functions of NK cells. Patients with myeloproliferative neoplasm treated with the inhibitor suffer from recurrent infections ( 38 ). We now extend these fi ndings by showing that ruxolitinib signifi cantly increases the amount of VEGFA in NK cells.…”

Section: Research Articlesupporting

confidence: 67%

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

et al. 2016

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Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-defi cient NK cells can be rescued by overexpression of BCL2. Our experiments defi ne STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-defi cient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verifi ed by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These fi ndings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis. SIGNIFICANCE:The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis. Cancer Discov; 6(4); ©2016 AACR . Ni and Cerwenka, p. 347. See related commentary by INTRODUCTIONNatural killer (NK) cells are innate lymphocytes that develop from a common lymphoid progenitor in the bone marrow ( 1 ). They represent the fi rst line of defense against infected, stressed, and malignant cells. Recent evidence has assigned distinct features and functions to tissue-specifi c NK cells ( 2 ). NK cells have organ-specifi c properties, such as distinct profi les of receptor expression or cytokine production ( 3 ). Uterine NK cells secrete high levels of VEGFA and are involved in placental vascularization. The physiologic functions of other organ-specifi c NK-cell subsets are less well understood ( 4 ). STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor PromotionDagmarAll aspects of NK-cell development are regulated by cytokines, their downstream signaling pathways, and transcriptional regulators. These include key cytokines such as IL2, IL12, IL15, IL18, and IL21 ( 5 ), most of which signal via the common γ chain ( 5 ) and activate the JAK-STAT pathway ( 6 ). JAK kinases (JAK1-3 and TYK2) bind to cytokine receptors and are activated by ligand/receptor binding. The activated kinase phosphorylates STAT transcription factors refs. 6,7 ).Consistent with its function as the major STAT protein downstream of IL7, IL2, and IL15, STAT5 is absolutely essential for conventional NK-cell development and survival; Stat5 Δ / Δ Ncr1-iCre Tg mice lack NK cells ( 8 ). It is also important for lymphoid cell development ( 9 ): STAT5 is constitutively active in a plethora of lymphoid malignancies ( 10 ). Recent studies have described somatic Stat5b mutations as active drivers of lymphoid mali...

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Section: Research Articlesupporting

confidence: 67%

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

et al. 2016

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“…Neuronal toxicity and lactic acidosis induced by the shift toward aerobic glycolysis have been observed in clinical trials of JAK 1/2 inhibitors and OPB-51602, respectively [20]. Moreover, infective complications of JAK inhibitor therapy have been convincingly linked to immune cell dysfunction, highlighting the role of STAT3 as an immune modulator [21]. It remains to be seen whether advances in structural analytical tools will lead to reduction in adverse effects of these novel compounds whilst preserving their efficacy.…”

Section: Expert Opinionmentioning

confidence: 99%

Do STAT3 inhibitors have potential in the future for cancer therapy?

Wong

Hirpara

Pervaiz

et al. 2017

Expert Opinion on Investigational Drugs

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“…JAK-STAT inhibitors have been extensively explored for cancer treatment, and more than 20 JAK-STAT inhibitors are being tested in clinical trials ( 5 ). The JAK-STAT pathway is also critical for lymphocyte activation, for instance by the cytokines IL2, IL12, IL15, and IL18 that mediate NK cell activity and/or development.…”

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confidence: 99%

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

Cerwenka

2016

Cancer Discovery

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Summary: Natural killer cells (NK) are commonly considered to be potent antitumor effector cells. The study by Gotthardt and colleagues challenges this concept and reveals that STAT5-defi cient/inhibited NK cells induce angiogenesis and promote tumor progression. These unexpected fi ndings shed new light on potential adverse effects of JAK-STAT inhibitors in the clinics. Cancer Discov; 6(4); 347-9. ©2016 AACR . Gotthardt et al., p. 414 (7). See related article byWithin the tumor microenvironment the interaction of tumor cells and immune cells critically shapes the progression of malignant disease ( 1 ). There is now increasing evidence that certain types of immune cells have the potential not only to effi ciently control, but also to promote tumor growth. For instance, M1 macrophages in tumors can directly kill tumor cells, whereas M2 macrophages support tumor angiogenesis and tumor development. So far, natural killer (NK) cells that effi ciently lyse tumor cells and produce infl ammatory cytokines such as IFN γ and TNF α are mainly associated with potent antitumor activity. Individuals with high NK cell activity have a lower risk to develop cancer ( 2 ). NK cell infi ltration in the tumor is frequently correlated with improved prognosis for patients with cancer, and in many mouse tumor models depletion of NK cells leads to accelerated tumor growth ( 1 ). These studies imply an important role of NK cells in tumor immunosurveillance and support clinical application of NK cell-based therapies in the clinic for cancer treatment. More recently, additional immunoregulatory functions have been attributed to NK cells. In infectious disease, NK cells were shown to kill activated T cells and to produce IL10 and TGF β , resulting in the downregulation of immune responses. Accordingly, a recent study revealed that high numbers of tumor-infi ltrating NK cells did not correlate with favorable prognosis and even might promote tumor progression ( 3 ). The mechanisms underlying NK cell-mediated tumor progression are poorly understood. Moreover, the molecular switches determining NK cell-mediated antitumor or protumor activity have not been elucidated. Strategies to counteract the potential tumor-promoting activity of NK cells could improve current NK cell-based antitumor therapies.The JAK-STAT pathway is activated in many tumor cells and promotes tumor progression. JAK-STAT inhibitors have been extensively explored for cancer treatment, and more than 20 JAK-STAT inhibitors are being tested in clinical trials ( 5 ). The JAK-STAT pathway is also critical for lymphocyte activation, for instance by the cytokines IL2, IL12, IL15, and IL18 that mediate NK cell activity and/or development. Accordingly, NK cells from patients with myeloproliferative neoplasm treated with a JAK inhibitor show impaired functional activity ( 5 ). A previous study by the Sexl lab ( 6 ) Δ / Δ Ncr1 -iCre Tg -Vav-Bcl2 mice showed severe functional defects in vitro , including impaired proliferation and decreased cytotoxicity and IFN γ production toward tumor...

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JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms

Cited by 160 publications

References 55 publications

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

Do STAT3 inhibitors have potential in the future for cancer therapy?

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

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